PKD1 was first reported in relation to biallelic polycystic kidney disease (PKD) in 2009 (Rossetti et al., PMID: 19165178). PKD1 has been previously classified as definitive for autosomal dominant polycystic kidney disease (ADPKD). Biallelic disease of two fully pathogenic PKD1 variants results in embryonic lethality and so viable biallelic cases must have at least one hypomorphic allele. This biallelic disease is a significant cause of very early onset PKD and can arise in a family with otherwise typical ADPKD (monoallelic family members). Individuals with a negative family history can have two hypomorphic alleles. At least seventeen unique variants (missense, nonsense, frameshift) that have been reported in thirteen probands in four publications (PMIDs: 19165178, 23624871, 30631912, 33168999) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached (PMIDs: 26139440, 20558538). This gene-disease relationship is also supported by two mouse models, biochemical function data, and expression data (PMIDs: 9326937, 23064367, 11106764, 31427367, 8981910, 11891195). In summary, PKD1 is definitively associated with autosomal recessive polycystic kidney disease (ARPKD-PKD1). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy GCEP on the meeting date 1/11/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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